The present invention relates to a novel intrauterine device, a method of reducing the rate of diffusion of active ingredients in said intrauterine device and a method of manufacturing said intrauterine device.
Today intrauterine devices (IUDs) are one of the safest and most efficient contraception used worldwide. IUDs have also been used to administer spermicides, as well as a variety of locally or systematically active medicaments. The devices have provided several advantages since their use is controlled by the female; they allow for a better regulated dose of drug without attention by the user; and they avoid the destruction (by the intestine and by first pass through the liver) of an appreciable portion of the daily dosage of some drugs compared to their orally delivered counterparts.
The devices, including intravaginal rings (IVRs), are typically formed from biocompatible polymers and contain a drug released by diffusion through the polymer matrix. The devices may be inserted into the vaginal cavity and the drug may be absorbed by the surrounding body fluid through the vaginal tissue. In some IVR designs, the drug is uniformly dispersed or dissolved throughout the polymer matrix (monolithic system). In other designs, the drug may be confined to an inner core within the ring (reservoir system). Monolithic systems are expected to show Fickian diffusion-controlled drug release whereby the release rate decreases with time. Reservoir systems may exhibit a zero order release of loaded drugs.
Several IVRs are commercially available today. As examples can be mentioned the Estring®, Femring®, and Nuvaring®, each of which provide controlled and sustained release of steroid molecules over several days/weeks.
These known vaginal rings have been found particularly useful for the release of steroids, whose relatively small molecular size and substantially water-insoluble nature permit effective permeation through the hydrophobic elastomer, such that therapeutic concentrations may be readily achieved in the body.
However, diffusion in polymers is complex and is known to depend on a number of different factors, e.g. temperature, pressure, the manufacturing process, the solubility of the drug in the polymer, the surface area of the drug reservoir, the distance the drug must diffuse through the device to reach its surface and the molecular weight of the drug. Consequently, it remains a challenge to understand, predict and control the diffusion of small and large molecules in polymer systems. In this respect, the use of intrauterine devices to deliver drugs requires a design that regulates the release rate so as to reliably provide the user with the appropriate daily dose throughout the lifetime of the device.
In reservoir systems, the drug first partitions into the membrane from the reservoir and then diffuses to the other side of the membrane, where it is taken up by the receiving medium. While the reservoir is saturated, a constant concentration gradient of drug is maintained in the membrane, the rate of drug flux is constant, and zero order release is achieved. However, when drug concentration in the reservoir falls below saturation, the gradient across the membrane and the release rate both decay.
In reservoir systems, the purpose of the membrane is to mediate diffusion of drug. Because of their simplicity of mechanism and their ability to produce zero order release, reservoir systems would seem to be highly advantageous. However, reservoir systems can be difficult to fabricate reliably. Furthermore, pinhole defects and cracks in the membrane surrounding the reservoir, can lead to dose dumping, i.e. unintended, rapid drug release over a short period of time.
These problems are avoided in monolithic systems, in which drug is loaded directly into a polymer, which now acts as both a storage medium and a mediator of diffusion. Drug is typically loaded uniformly into monolithic devices, and the release is controlled by diffusion through the monolithic matrix material or through aqueous pores.
A problem with reservoir systems, and even more with monolithic devices, are that they typically exhibit an initial burst, i.e. excessive release of drug in the first few days. This may, depending on the concentration of released drug, cause undesirable side effects such as nausea or vomiting.
Several attempts have been made to overcome said problem, e.g as disclosed in WO9804220, which teaches a vaginal ring wherein the drug-containing core is positioned in a hollow internal channel of the device immediately prior to use. However, since it is difficult and troublesome to place the core in the ring in a reliable and safe manner, there is considerably production cost involved with said ring and there may be significant variations between different rings.
It is e.g. further believed that when some polymers are exposed to degradation agents such as oxygen and moisture, different polymer morphologies can develop. The differences in polymer morphology may cause the release rate of the active agent from the IUD to vary significantly. As a consequence of the inconsistent release rate profiles among different IVRs, clinical complications can occur. Additionally, when IVRs are stored, the release rate from the IVRs can change during the storage time, known as “release rate drift.”
Furthermore, with passing time, release rate decreases, as drug that is deeper inside the monolith device must diffuse to the surface, since it has farther to travel, and the quadratic relation between distance and time becomes important. Since the geometric factor is essential in this respect, the effects can be minimised by using other geometric shapes or hemisphere monoliths to provide near-zero-order release, but such devices are neither easy nor inexpensive to fabricate.
As the amount of available drug decreases over time and with distance from the surface, the drug is often added in larger concentrations than actually required from a therapeutically point of view. The effect being that larger dosages of the active drug are released from the device. This will not only result in a higher production costs, but the user will also be subjected to higher dosages of the drug than is needed or desired.
Thus, there is a demand for a device and a method that reduces the variability of the release rate of active agents among IUDs, including IVRs, over time. Accordingly, there is a requirement for providing IUDs in which the known problems relating to complicated and expensive manufacturing processes, dose dumping and initial drug burst are eliminated, and which at the same time reduces the release rate of the drug in order to provide smaller IUD and/or IUD having a prolonged effective duration.